Over the past two decades, nanotherapeutics has made a significant impact on the field and success of cancer therapeutics. Despite this, the American Cancer Society estimates that in 2014, there will be an estimated 1.7 million new cancer diagnoses made and an estimated 600,000 deaths attributed to cancer in the United States. Chemotherapy is the most common anticancer treatment, but is frequently discontinued due to toxic side effects or the development of drug resistance. See e.g. Lin et al., Molec. Ther. 2003, 8:441-448.
One strategy to combat drug resistance is to combine at least two chemotherapeutic agents, each having different molecular targets to delay the cancer adaptation process. Another strategy to combat drug resistance is to combine at least two chemotherapeutic agents, each having the same molecular target or otherwise interacting in such a way that the cocktail of chemotherapeutic agents has a greater efficacy and/or target selectivity than any of the individual chemotherapeutics alone. See e.g. Lee and Nan, J. Drug Delivery. 2012. ID 915375. Although in many situations the overall effective dose of each chemotherapeutic is less when administered in a cocktail as compared to administration of each chemotherapeutic individually, discontinuation of combinational therapy due to toxic side effects is still a problem. This is because most combinational therapies are still systemically administered.
Combining traditional drug-based chemotherapy with gene therapy is another promising strategy for the treatment of cancer. See e.g. Lin et al., 2012, Yadav et al., Cancer Chemother. Pharmacol. 2009, 63:711-722, and “Nanomaterials in Drug Delivery, Imaging and Tissue Engineering, ed. Tiwari and Tiwari, Wiley-Scrivener, 2013. Approaches that utilize viral vectors for gene transfer suffer from low transduction efficiencies and their clinical value is diminished as a result of immunogenicity of the vectors, oncogenic risk, and hepatotoxicity. See Gao et al. Aaps J. 2007. 9:E92-E104. Further, these approaches require the gene therapy molecule and the chemotherapeutic molecule to be delivered separately from one another. See e.g. Lin et al., 2012. As such, this approach typically requires increased dosages of both the gene therapy vectors and chemotherapeutic molecule to increase the probability that both molecules end up in the same cells. This results in the potential for increased toxic side effects from the treatment.
MDR-1 targeting small interfering RNA and paclitaxel encapsulated by poly(ethylene oxide)-modified poly(beta-amino ester) or poly(ethylene oxide)-modified (epsilon-caprolactone) nanoparticles, respectively, were shown to increase the cytotoxic activity of paclitaxel in paclitaxel sensitive cancer cells. (Yadav et al., Cancer Chemother. Pharmacol. 2009. 63:711-722). However, this method still does not ensure delivery to the same cell as the gene therapy molecule and the chemotherapeutic drug are still delivered on separate platforms.
A few preliminary in vitro research efforts have focused on simple non-viral vectors for simultaneous drug and gene therapy, such as cationic liposomes (e.g. Saad et al., Nanomed. 2008. 3:761-776), cationic core-shell nanoparticles (e.g. Wang et al., Nat. Mater. 2006. 5:791-796), cationinc micells (e.g., Zhu et al., Biomaterial. 2010.31:2408-2416), dendrimers (e.g. Kaneshio and Lu. Biomaterial. 2009. 30:5660-5666), and mesoporous silica nanoparticles (e.g. Chen et al. Small. 2009. 5:2673-2677. Although these combination therapies are more effective at killing cancer cells than the chemotherapeutic drugs alone, they are also more likely to damage healthy tissue when delivered systemically. Therefore, there exists a need for targeted delivery of therapeutic agents, including combination therapies, to improve therapeutic efficacy while reducing toxic side effects.
Additionally, heterogeneity of cancers makes it difficult to predict which therapy or combination of therapies will be efficacious for a particular cancer in an individual. Therefore, it is common that a patient may have to try several treatment regimens before one (if any) are found to be effective. This often leads to noncompliance with therapy and poor success rates. In some instances, the tumors are biopsied and tested for drug resistance and sensitivities in vitro. However, results from in vitro drug efficacy studies, even on biopsied tumors, are of limited value because they do not effectively mimic the in vivo tumor environment. Further, biopsy assays do not permit for non-invasive monitoring of the effectiveness of a treatment regimen.
As such there is an urgent need to develop a single platform that can efficiently deliver therapeutic drugs and gene therapy molecules that allow for non-invasive treatment monitoring.